The goal of these proposed studies is to develop the laboratory opossum (Monodelphis domestica) as an animal model for investigating metabolic and molecular mechanisms of high and low responses to dietary lipids. Partially inbred strains of opossums exhibit individual differences in very low (VLDL) and low (LDL) density lipoprotein cholesterol concentrations in response to a high cholesterol and high fat (HCHF) diet. These differences are under strong genetic control and a major gene explains 80% of the variability. Thus, the laboratory opossum may be a unique model for investigating the metabolic and genetic basis of lipemic response to diet. An important question that is proposed to answer is whether the major gene is responsive to dietary cholesterol or dietary fat or a combination of both. Based on pervious work, it is hypothesized that the difference in LDL cholesterol concentrations is due to strain differences in LDL apoB production. To test this hypothesis, LDL apoB synthesis will be conducted, cholesterol absorption and bile acid composition in high and low responding opossums on the chow and HCHF diets will be measured. Dietary cholesterol changes the expression and activity of a number of hepatic genes, and a mutation in any of these genes may affect the handling of excess dietary cholesterol by the liver. Therefore, the expression of a major hepatic and extrahepatic cholesterol responsive genes between high and low responding opossums will be measured and compared. If the activity or the expression of a major cholesterol responsive gene is associated with the lipemic responsiveness, a search for a polymorphism by single-strand conformation polymorphism analysis will be done. If a polymorphism in the gene is also associated with the response, selectively bred animals will be genotyped and these data used for linkage analysis to determine if this is the major gene detected by genetic analysis. It is possible that this gene may also be a major determinant of die-induced hyperlipidemia in humans. However, even if this is not the case, these studies are likely to lead to new strategies in the management of diet-induced hyperlipidemia and atherosclerosis in humans.